Search Results (861)

Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung carcinoma (NSCLC), commonly metastasizes to the brain, particularly in advanced stages. Since brain metastases (BMs) are a leading cause of morbidity and mortality in LUAD patients, their early detection is critical, necessitating the identification of reliable biomarkers. Gangliosides (GGs), a class of bioactive glycosphingolipids involved in cell signaling, adhesion, and immune regulation, have emerged as promising candidates for diagnostic and therapeutic targeting in LUAD-associated brain metastases (BMLA). In this context, ion mobility spectrometry mass spectrometry (IMS-MS) was employed here to analyze GG alterations in BMLA tissues compared to healthy cerebellar control. The results revealed marked differences, including a reduction in the total number of species, altered sialylation profiles, and variations in fatty acid chain length and sphingoid base hydroxylation. GM3, a monosialodihexosylganglioside, was significantly overexpressed in BMLA, supporting its role in tumor progression via immune evasion and oncogenic signaling. Elevated levels of the brain-specific GT1 ganglioside further point to its possible role as a metastasis-associated biomarker, while the presence of asialogangliosides, absent in normal brain, suggests adaptation to the brain microenvironment. Structural modifications such as O-acetylation, fucosylation, and CH₃COO⁻ were more frequent in BMLA, being associated with aggressive tumor phenotypes. Ceramide profiles revealed increased levels of proliferative C16- and C24-ceramides and decreased pro-apoptotic C18-ceramide. Additionally, GM3(d18:1/22:0) and GD3(d18:1/16:0), identified as potential BMLA biomarkers, were structurally characterized using (−) nanoelectrospray ionization (nanoESI) IMS collision-induced dissociation tandem MS (CID MS/MS). Collectively, these findings highlight the clinical potential of GGs for early diagnosis and targeted therapy in BMLA. Full article

Background and Clinical Significance: Adults suffering from cerebellar metastases are often at high risk for rapid deterioration of their neurological status because the posterior fossa has limited compliance and the location of these metastases are close to the brain stem and important cerebrospinal fluid (CSF) pathways. In this paper, we present a longitudinal, patient-centered report on the history of an elderly individual who suffered from cognitive comorbidities and experienced a sudden loss of function in her cerebellum. Our goal in reporting this case is to provide a comparison between the patient’s pre-operative and post-operative neurological examinations; the imaging studies she had before and after surgery; the surgical techniques utilized during her operation; and the outcome of her post-operative course in a way that will be helpful to other patients who have experienced a similar situation. Case Presentation: We report the case of an 80-year-old woman who initially presented with progressive ipsilateral limb-trunk ataxia, impaired smooth pursuit eye movement, and rebound nystagmus, but preserved pyramidal and sensory functions. Her quantitative bedside assessments included some of the components of the Scale for the Assessment and Rating of Ataxia (SARA), and a National Institute of Health Stroke Scale (NIHSS) score of 3. These findings indicated dysfunction of the left neocerebellar hemisphere and possible dentate nucleus involvement. The patient’s magnetic resonance imaging (MRI) results demonstrated an expansive mass with surrounding vasogenic edema and marked compression and narrowing of the exits of the fourth ventricle which placed the patient’s CSF pathways at significant risk of occlusion, while the aqueduct and inlets were patent. She then underwent a left lateral suboccipital craniectomy with controlled arachnoidal CSF release, preservation of venous drainage routes, subpial corticotomy oriented along the lines of the folia, stepwise internal debulking, and careful protection of the cerebellar peduncles and dentate nucleus. Dural reconstruction utilized a watertight pericranial graft to restore the cisternal compartments. Her post-operative intensive care unit (ICU) management emphasized optimal venous outflow, normoventilation, and early mobilization. Histopathology confirmed the presence of metastatic carcinoma, and staging suggested that the most likely source of the primary tumor was the lungs. Immediately post-operation, computed tomography (CT) imaging revealed a smooth resection cavity with open foramina of Magendie and Luschka, intact contours of the brain stem, and no evidence of bleeding or hydrocephalus. The patient’s neurological deficits, including dysmetria, scanning dysarthria, and ataxic gait, improved gradually during the first 48 h post-operatively. Upon discharge, the patient demonstrated an improvement in her limb-kinetic subscore on the International Cooperative Ataxia Rating Scale (ICARS) and demonstrated independent ambulation. At two weeks post-operation, CT imaging revealed decreasing edema and stable cavity size, and the patient’s modified Rankin scale had improved from 3 upon admission to 1. There were no episodes of CSF leakage, wound complications, or new cranial nerve deficits. A transient post-operative psychotic episode that was likely secondary to her underlying Alzheimer’s disease was managed successfully with short-course pharmacotherapy. Conclusions: The current case study demonstrates the value of anatomy-based microsurgical planning, preservation of venous and CSF pathways, and targeted peri-operative management to facilitate rapid recovery of function in older adults who suffer from cerebellar metastasis and cognitive comorbidities. The case also demonstrates the importance of early multidisciplinary collaboration to allow for timely initiation of both adjuvant stereotactic radiosurgery and molecularly informed systemic therapy. Full article

Maximal safe surgical resection is a foundational principle in brain tumor surgery. To date, many intraoperative modalities have been developed to help facilitate the identification of brain tumor versus normal brain tissue so that surgical resection is maximized but limited to the boundaries of the tumor for preservation of neurological function. Of note, Raman spectroscopy has been adapted into one of these modalities because of its ability to provide rapid, non-destructive, label-free intraoperative evaluation of tumor borders and molecular classifications and help guide surgical decision-making in real time. In this review, we performed a literature review of the landmark studies incorporating Raman spectroscopy into neurosurgical care to highlight its current applications and limitations. In this modern day, Raman spectroscopy is able to detect tumor cells intraoperatively for primary glial neoplasms, meningiomas, and brain metastases with greater than 90% accuracy. For glioma surgery, a major recent advancement is the ability to detect different mutations intraoperatively, specifically IDH, 1p19q co-deletion, and ATRX, given their implications on survival and how much extent of resection should be ideally achieved. With recent advancements in artificial intelligence and their integration into stimulated Raman histology, many of these tasks can be completed in as fast as ~10 s and on average 2–3 min. Despite the incorporation of artificial intelligence, spectral data can still be heavily influenced by background noise, and its preprocessing has significant variability across platforms, which can impact the accuracy of results. Overall, Raman spectroscopy has significantly changed the intraoperative workflow of brain tumor surgery, and this review highlights the capabilities that neurosurgeons can currently take advantage of in their practice, the existing data to support it, and the areas that researchers can further optimize to improve accuracy and patient outcomes. Full article

Background/Objectives: Posterior fossa brain metastases (PFBMs) pose particular risks owing to their proximity to the brainstem and fourth ventricle. We evaluated the safety (treatment-related complications), local effectiveness, and procedural efficiency of volumetric modulated arc therapy (VMAT)-based stereotactic radiosurgery (VMAT-SRS) for PFBMs. Methods: This single-centre, retrospective study derived a PFBM subgroup from an overall institutional cohort of 123 patients treated with VMAT-RapidArc SRS/fSRS. The doses were 12–20 Gy (single fraction) or 5 × 6 Gy (selected cases). Local response (mRECIST) and predefined safety endpoints (symptomatic oedema with brainstem/IV-ventricle compromise, obstructive hydrocephalus, haemorrhagic transformation, CSF diversion, and urgent neurosurgery) were assessed. Overall survival and procedural time were analysed. Results: Thirty-one patients (39 lesions) were included; 76.9% of them received single-fraction SRS. In addition, 74.2% of patients had supratentorial metastases with posterior fossa involvement. Kaplan–Meier overall survival at 6, 12, 24, and 48 months was 74%, 58%, 26%, and 9.7%, respectively; the median survival time was 12.6 months. Among evaluable lesions, local control was 84.5% (per-lesion response: 15.5% PD, 28.1% SD, 34.4% PR, and 22.0% CR). No clinically significant posterior fossa local complications were observed. Three patients developed radiation-induced leukoencephalopathy after whole-brain radiotherapy (WBRT) and radiosurgery for synchronous supratentorial metastases. The median procedural time was 25.0 min (IQR 9.0) with one isocentre versus 52.5 min (IQR 9.75) with two. Conclusions: VMAT-SRS/fSRS for PFBMs achieved high local control, very low posterior fossa toxicity, and favourable procedural efficiency, supporting its use as a safe, rapid, frameless alternative to WBRT and other radiosurgical platforms such as Gamma Knife in appropriately selected patients. Full article

Background/Objectives: Brain metastases (BM) are common in small cell lung cancer (SCLC) and portend poor outcomes. Contemporary determinants of survival in the modern treatment era remain incompletely defined. We evaluated factors associated with overall survival (OS) among patients with SCLC and BM using a recent, nationally representative dataset. Methods: We identified adults diagnosed with SCLC and brain metastases between 2018 and 2020 in the National Cancer Database (NCDB). Demographic, clinical, treatment, and survival data were extracted for analysis. Unadjusted OS was estimated using Kaplan–Meier methods. Multivariable Cox proportional hazards models identified factors associated with mortality, with proportional hazards (PH) assessed using scaled Schoenfeld residuals. Complementary Accelerated Failure Time (AFT) modeling was performed to confirm robustness. Results: Of 62,671 SCLC cases, 11,074 (17.7%) had BM, including 32.6% with brain-only disease. Median overall survival (mOS) was 6.6 months (95% CI, 6.47–6.87); patients with brain-only disease had an mOS of 8.8 months (8.38–9.26), compared with 5.95 months (5.75–6.18) for those with concurrent extracranial metastases. In multivariable analysis, age ≥ 65 years (HR 1.13, p < 0.001) was associated with higher mortality, whereas female sex (HR 0.87, p < 0.001), Black (HR 0.88, p = 0.001), Asian (HR 0.80, p = 0.022), and Hispanic (HR 0.87, p = 0.008) patients had lower hazards. Worse outcomes were associated with public or no insurance, lower income, non-academic facilities, and extracranial metastases; educational attainment was not significant. Proportional hazards assumptions were largely met with minor deviations, and AFT modeling confirmed consistent results. Treatment modality remained independently associated with survival in both models. Conclusions: In this contemporary national cohort, survival among patients with SCLC and brain metastases was influenced by multiple clinical, sociodemographic, and treatment factors, including age, sex, insurance status, facility type, and extent of metastatic disease. Treatment modality remained an independent predictor of survival. These results provide updated real-world benchmarks and highlight the need for prospective studies to define optimal management strategies in this high-risk population. Full article

Small cell lung cancer (SCLC) is an aggressive malignancy with a high incidence of brain metastases. Prophylactic cranial irradiation (PCI) was developed to reduce central nervous system (CNS) relapses and has been shown to improve survival, particularly in limited-stage disease. The pivotal Auperin meta-analysis and subsequent studies confirmed its role in patients achieving a complete response to initial therapy. In extensive-stage SCLC, earlier trials demonstrated reduced brain metastases and modest survival gains, but more recent studies incorporating routine magnetic resonance imaging (MRI) surveillance failed to show overall survival benefits, supporting MRI monitoring with salvage therapy as an alternative. Neurocognitive toxicity remains the major limitation of PCI, especially in older adults. Common effects include memory impairment, cognitive changes, and a reduced quality of life. Advances such as hippocampal avoidance PCI and neuroprotective strategies like memantine have shown the ability to mitigate long-term decline. Modern radiotherapy techniques, including intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), enable the precise sparing of critical structures while maintaining intracranial control. The integration of immunotherapy has shifted treatment paradigms in SCLC. While checkpoint inhibitors have improved systemic outcomes, their impact on brain relapses and interactions with PCI remain uncertain. This review provides an overview of the evolution of PCI in SCLC, while emphasizing current challenges and future directions. Full article

Small-cell lung carcinoma (SCLC) remains one of the most aggressive lung cancers and continues to pose a major challenge for precision oncology. Despite its morphological uniformity, SCLC exhibits marked molecular heterogeneity with recurrent, potentially targetable genomic alterations. Comprehensive profiling is often hindered by limited tissue availability and the need for rapid therapeutic intervention. We performed genomic profiling of 55 primary and metastatic SCLC samples using a 324-gene hybrid-capture next-generation sequencing panel. Consistent with prior reports, nearly all tumors exhibited biallelic TP53 and RB1 inactivation. Recurrent alterations involved the PI3K/Akt/mTOR pathway (62%), chromatin regulators (42%), and NOTCH signaling genes (15%). PTEN mutations were enriched in brain metastases. Frequent copy-number gains affected SOX2, NKX2-1, MYC-family genes, and CCNE1. Two novel recurrent amplifications of potential clinical significance were identified: TYRO3 (33%) and SDHA (13%). TYRO3, a TAM family receptor tyrosine kinase, and SDHA, a mitochondrial enzyme involved in succinate metabolism, may contribute to tumor progression and represent emerging therapeutic vulnerabilities. These findings underscore the genomic diversity of SCLC and highlight the potential utility of broad next-generation sequencing in uncovering new molecular targets for precision therapy. Full article

Background: Stereotactic radiotherapy (SRT) is a promising treatment option for patients with multiple brain metastases (BMs). Using one isocenter instead of a separate isocenter for each BM can reduce the treatment time. This work compares the calculated dose in the treatment planning system with the measured dose using film dosimetry of single-isocenter multi-target (SIMT) SRT for multiple BM. Methods: Fifty patients with 4 to 18 BMs (median = 6, in total 356 BMs) were treated with a single-isocenter non-coplanar LINAC-based treatment with six VMAT arcs. Treatment was performed using RayStation and Elekta Versa HD with Agility multileaf collimator, including a 6D robotic couch. Patient-specific QA measurements were performed with an in-house developed phantom using three layers of GafChromic EBT3 film. Film measurements were analyzed in DoseLab using global gamma with 3% and 1 mm distance-to-agreement criteria. Additionally, secondary dose calculations in Mobius3D were performed with similar gamma criteria. Results: The mean total Paddick conformity index and gradient index were 0.7 ± 0.10 and 5.2 ± 1.9, respectively. Monitor units used were 6321 ± 2510, and mean irradiation time was 600 ± 90 s. The mean global gamma passing rate for all measured films was 94.5 ± 4.6% with 3% and 1 mm criteria, while that of the dose calculations in Mobius3D was 98.2 ± 1.2% with the same criteria. A dependence of gamma passing rates of film measurements on the total PTV volume was observed, whereas such dependence was minimal for Mobius3D. Conclusions: The results demonstrate good agreement between the TPS, film measurements, and independent dose calculations, supporting the dosimetric accuracy of single-isocenter multi-target SRT for treating multiple BMs. Full article

Small-cell lung cancer (SCLC) is an aggressive malignancy that exhibits high prevalence for brain metastases. Furthermore, chemotherapy and metastasis-preventive approaches are also linked to neurotoxicity, further aggravating cognitive impairment. Despite evidence supporting structural and functional brain alterations in SCLC, the application of machine learning (ML) to new connectivity biomarkers has remained unexplored. This study is—to the best of our knowledge—the first to apply ML to structural brain connectomics in SCLC, using diffusion tensor imaging (DTI) to identify features discriminating between post-chemotherapy SCLC patients and healthy controls. Specifically, we constructed structural networks via deterministic tractography, applying an adapted feature reduction technique to identify the most informative connections without selection bias. This process isolated 16 connections involving 26 brain regions, predominantly in the frontal, temporal, and parietal lobes, showcasing primarily intra-hemispheric and left-lateralized alterations. Our optimal model leveraged a Gaussian Support Vector Machine (SVM), achieving a weighted accuracy of 0.92, a sensitivity of 0.93, a specificity of 0.91, and an area under the curve of 0.94. The selected feature subset retained high performance when tested with other classifiers, confirming its robustness. Our findings differ from prior studies based on statistically derived features, highlighting the ML-driven connectomics’ potential in uncovering DTI-derived SCLC patterns, offering interpretable insights for neuroimaging-based diagnostics. Full article

Background: This study was designed as a dosimetric feasibility analysis to compare hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) using 3D-CRT, IMRT, and VMAT techniques, with particular attention to clinical applicability in resource-limited settings. While 3D-CRT was used as a reference for conventional WBRT, the primary aim was to determine whether IMRT can serve as an effective and accessible alternative to VMAT for HA-WBRT in centers without advanced technology infrastructure. Methods: Fifteen patients undergoing WBRT for symptom relief were planned using 3D-CRT, IMRT, and VMAT on the Elekta Monaco 6.1.4.0 system. Key organs at risk (OARs) such as the optic nerves, chiasm, eyes, and lenses were considered in the treatment planning. Plans were evaluated based on PTV dose distribution, Conformity Index (CI), Homogeneity Index (HI), and OAR dose constraints (RTOG 0933, NRG-CC001). Gamma pass rate analysis (3%/3 mm) was performed for the IMRT and VMAT plans. Results: IMRT and VMAT significantly reduced the hippocampal dose compared to 3D-CRT, with similar PTV coverage and OAR sparing. The mean D_max for the hippocampus was 15.4 Gy for IMRT and 15.5 Gy for VMAT compared to 31.2 Gy for 3D-CRT. The D100% for the hippocampus was 7.5 Gy for IMRT and 7.6 Gy for VMAT, both well below the RTOG 0933 threshold of 9 Gy, while 3D-CRT delivered 30.3 Gy. Additionally, IMRT and VMAT delivered lower doses to the optic nerves and chiasm. QA results showed gamma pass rates above 96% for all plans. This study focused solely on treatment-planning and dosimetric feasibility without evaluating patient outcomes or clinical follow-up. Conclusions: HA-WBRT with IMRT and VMAT significantly reduced the hippocampal dose while maintaining optimal PTV coverage. VMAT is preferred for its balance of efficacy, protection, and treatment time, while IMRT represents a feasible approach for facilities without VMAT, though it requires stricter dose control and longer treatment times. Full article

Purpose: Brain metastases occur in up to 30% of patients with advanced cancer and remain a major clinical challenge. While WBRT was historically the standard treatment, it provided limited survival benefit and significant neurocognitive toxicity, leading to increasing use of stereotactic radiosurgery (SRS). Recent advances with single-isocenter, multi-target (SIMT) dynamic conformal arc (DCA) techniques on modern linear accelerators have enabled efficient treatment of numerous lesions within a single session, though concerns regarding geometric accuracy persist. This study aimed to evaluate local control outcomes and influencing factors following DCA-SIMT radiosurgery in patients with multiple brain metastases. Methods: We retrospectively analyzed 195 brain metastases treated using single-isocenter, multi-target dynamic conformal arc (DCA-SIMT) stereotactic radiosurgery on a Varian TrueBeam LINAC between August 2018 and September 2020. Treatment planning was performed with Brainlab Elements MultiMets software, version 2.0 and image guidance with ExacTrac. Local control was assessed on MRI according to BM-RANO criteria, while radiation-induced contrast enhancements (RICE) were identified using multiparametric MRI. The median follow-up duration was 12 months. Statistical analyses included chi-square and ROC analyses, with p < 0.05 considered statistically significant. Results: A total of 195 brain metastases in 37 patients were analyzed. Local control at 6 months was achieved in 93% of lesions, with complete or partial response in 82%. Distance-to-isocenter (DTI), gradient index (GI), and target volume (GTV/PTV) were not associated with local control. In contrast, conformity index (CI) < 1.42 predicted better treatment response (AUC = 0.698, p = 0.0006). Margin expansion ≥ 0.5 mm was associated with improved local control (p = 0.049), while higher margins did not further improve outcomes. Prescription dose showed no significant impact. The addition of immunotherapy or targeted therapy within 4 months post-SRS significantly increased the likelihood of radiographic response (OR = 2.55, p = 0.030), with the strongest association observed in lung adenocarcinoma patients (p < 0.001). Conclusions: DCA-SIMT stereotactic radiosurgery achieves high local control in patients with multiple brain metastases. Conformity index, minimal margin expansion, and systemic therapy influenced outcomes, whereas distance-to-isocenter and dose did not. Further validation is needed to optimize margins in high-DTI scenarios. Full article

Background: Brain metastases (BM) are a common and serious complication in cancer patients, particularly those with lung, breast, or melanoma primaries. As systemic therapies extend survival, the incidence of BM has increased, necessitating improved diagnostic and treatment strategies. Recent advances in neuroimaging and therapy have significantly enhanced the ability to diagnose and manage these lesions with greater precision. Methods: This article summarizes current diagnostic imaging modalities—Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Perfusion-Weighted Imaging (PWI), and Magnetic Resonance Spectroscopy (MRS) and their roles in distinguishing tumor progression from treatment effects. It also compares the efficacy of therapeutic options including Whole-Brain Radiation Therapy (WBRT), Stereotactic Radiosurgery (SRS), and systemic therapies such as targeted drugs and immunotherapies. Outcomes were evaluated based on local tumor control and overall survival. Results: Advanced imaging techniques like PWI, MRS, and PET improve diagnostic accuracy by providing functional and metabolic information beyond standard MRI. Therapeutically, SRS offers better local control and fewer cognitive side effects than WBRT for patients with limited metastases. Targeted and immune-based therapies have shown improved survival in patients with specific genetic mutations, supporting a personalized treatment approach. Conclusions: The integration of advanced imaging and individualized therapies has improved diagnosis, treatment decisions, and outcomes in patients with brain metastases. Ongoing research is essential to refine these tools and approaches, further optimizing patient care and quality of life. Full article

Background/Objectives: The goal is to provide a straightforward framework for generating SRS-SRT plans that reliably meet high-quality dosimetric standards. That posed some questions such as which plan quality metrics should be utilized to evaluate a plan, what influences plan quality metrics the most, and finally, how to best optimize plan geometry. Our work has primarily concentrated on the second question, guided by our clinical experience. Methods: A dataset for statistical analysis was compiled by retrospectively reviewing 200 individual SRS-SRT target volumes from two centers. From the gathered data, several Linear Regression models were generated to assess the variability of plan quality metrics using statistical analysis. The most important regressor in the models were revealed to be target volume (TV), followed by a flag type variable that indicates whether the plan used to treat the referenced target contained multiple targets (MT) or not. Results: Every doubling of TV lowers Gradient Index (GI) sharply (−0.55 to −0.17) while Gradient Measure (GM) increases moderately (+0.024 cm to +0.07 cm). The model explains 85% of the variation in GI (R² = 0.85) and 84% of GM. Conclusions: In small lesions, GI seems to be a more sensitive evaluation metric for sub-CC SRS targets, compared to GM. Dose per fraction appeared to have had no significant effect. Treating multiple targets in the same plan appears to add an average of +0.19 to GI, independent of volume, while for GM by +0.027 cm. Full article

Background/objective: Carboplatin, pemetrexed, and pembrolizumab are established as a key first-line regimen for metastatic non-small cell lung cancer, although selecting the optimal therapy for each patient remains challenging in real-world clinical practice. This retrospective multicenter study compared the efficacy and safety of two atezolizumab-based combination regimens, ACnP (carboplatin, nab-paclitaxel, atezolizumab) and ABCP (carboplatin, paclitaxel, bevacizumab, atezolizumab), in patients with non-small cell lung cancer in real-world clinical practice. Methods: A total of 91 patients treated between May 2018 and December 2023 at six Japanese hospitals were analyzed: 40 received ACnP and 51 received ABCP. Patient characteristics, treatment outcomes, and adverse events were compared, with subgroup analyses adjusted by inverse probability of treatment weighting using propensity scores. Results: The objective response rates were 55.0% with ACnP and 45.1% with ABCP. Median progression-free survival was 5.5 months for ACnP and 6.9 months for ABCP, while median overall survival was 16.2 and 18.3 months, respectively. Subgroup analyses showed significantly improved progression-free survival with ABCP in patients with brain metastases, liver metastases, EGFR-positive tumors, PD-L1-positive tumors, and impaired renal function (CCr < 45 mL/min). ABCP also conferred overall survival benefits in patients with brain and liver metastases. However, ACnP was associated with a lower incidence of neutropenia, peripheral neuropathy, and skin rash. Conclusions: These findings suggest that ABCP may offer superior efficacy in specific non-small cell lung cancer subgroups, while ACnP remains a valuable option for patients requiring a more tolerable safety profile. Full article

ROS1 gene rearrangements define a distinct molecular subtype of non-small cell lung cancer (NSCLC), occurring in approximately 2% of cases and frequently associated with younger age, non-smoker status, and a high incidence of brain metastases. The discovery of ROS1 as an oncogenic driver has led to the development of targeted tyrosine kinase inhibitors (TKIs). Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape. Full article